Stereoselective process for the production of dioxolane nucleoside analogues

Abstract

The present invention relates to a process for producing compounds of formula (I) and (VII); said process comprising the steps of: a) subjecting a compound of formula (II) to an enzymatic diastereomeric resolution in the presence of a suitable amount of enzyme chosen from Pig Liver Esterase or Porcine Pancreatic Lipase b) recovering said compounds of formula (I) and (VII). The invention also provides a process for producing compounds of formula (III) and (X); said process comprising the steps of: a) subjecting a compound of formula (IV) to an enzymatic diastereomeric resolution in the presence of a suitable amount of enzyme chosen from Candida Antarctica “A” lipase, Candida Antarctica “B” lipase, Candida Lypolitica Lipase or Rhizomucor Miehei Lipase b) recovering said compound of formula (III) and (X).

1. A process for producing a compound of formula I and a compound of formula VII: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 3-10  heterocycle, C 6-12  aralkyl or C 3-10  heteroaralkyl, and 
 R 2  is CO—C 1-6  alkyl, CO—C 6-12  aryl, CO—C 1-6  alkoxy, CO—C 6-12  aryloxy, or CO—C 6-12  arylalkyl; 
 
       said process comprising:
 a) subjecting a compound of formula II: 
 
       
         
           
           
               
               
           
         
       
       to an enzymatic diastereomeric resolution in the presence of a suitable amount of Pig Liver Esterase enzyme or Porcine Pancreatic Lipase enzyme, wherein said resolution is conducted in the presence of a solvent selected from water, C 1-12  alkanol, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfonamide, N-methylpyrrolidone, isooctane, t-butylmethyl ether, and mixtures thereof; and
 b) recovering compounds of formula I and formula VII. 
 
     
     
       2. The process according to  claim 1 , wherein R 1  is C 1-12  alkyl. 
     
     
       3. The process according to  claim 1  wherein R 2  is CO—C 1-6  alkyl. 
     
     
       4. The process according to  claim 1 , wherein R 2  is CO—C 6-12  aryl. 
     
     
       5. The process according to  claim 1 , wherein the enzyme is Pig Liver Esterase. 
     
     
       6. The process according to  claim 1 , wherein the enzyme is Porcine Pancreatic Lipase. 
     
     
       7. The process according to  claim 1 , further comprising:
 a) replacing the functional group at position C4 of the compound of formula I with B to produce a compound of formula V: 
 
       
         
           
           
               
               
           
         
       
       wherein B is purine or pyrimidine base;
 b) removing the group R 2  of said compound of formula V; and 
 c) recovering a compound of formula VI: 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       8. The process according to  claim 7 , wherein B is: 
       
         
           
           
               
               
           
         
       
       R 3  is H, C 1-6  alkyl, C 1-6  acyl, or CO—R 9 ; 
       R 9  is H or C 1-6  alkyl; 
       R 4  and R 5  are each independently H, C 1-6  alkyl, bromide, chloride, fluoride, iodide or CF 3 ; and
 R 6 , R 7  and R 8  are each independently H, bromide, chloride, fluoride, iodide, amino, hydroxyl, or C 3-6  cycloalkylamino. 
 
     
     
       9. A process according to  claim 1 , wherein R 1  is C 1-12  alkyl and R 2  is CO—C 6-12  aryl. 
     
     
       10. A process according to  claim 1 , wherein R 1  is methyl and R 2  is benzoyl. 
     
     
       11. A process for producing a compound of formula III and a compound of formula X: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein
 R 11  is C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 3-10  heterocycle, C 6-12  aralkyl or C 3-10  heteroaralkyl; and 
 R 12  is CO—C 1-6  alkyl, CO—C 6-12  aryl, CO—C 1-6  alkoxy, CO—C 6-12 aryloxy, or CO—C 6-12  arylalkyl, 
 
       said process comprising:
 a) subjecting a compound of formula IV: 
 
       
         
           
           
               
               
           
         
       
       to an enzymatic diastereomeric resolution in the presence of a suitable amount of an enzyme, wherein said enzyme is  Candida Antarctica  “A” lipase,  Candida Antarctica  “B” lipase,  Candida Lypolitica  Lipase, or  Rhizomucor Miehei  Lipase, wherein said resolution is conducted in the presence of a solvent selected from water, C 1-12 alkanol, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfonamide, N-methylpyrrolidone, isooctane, t-butylmethyl ether, and mixtures thereof; and
 b) recovering compounds of formula III and formula X. 
 
     
     
       12. The process according to  claim 11 , wherein R 11  is C 1-12  alkyl. 
     
     
       13. The process according to  claim 11 , wherein R 12  is CO—C 1-6  alkyl. 
     
     
       14. The process according to  claim 11 , wherein R 12  is CO—C 6-12  aryl. 
     
     
       15. The process according to  claim 11 , wherein the enzyme is  Candida Antarctica  “A” lipase. 
     
     
       16. The process according to  claim 11 , wherein the enzyme is  Candida Antarctica  “B” lipase. 
     
     
       17. The process according to  claim 11 , wherein the enzyme is  Candida Lypolitica  Lipase. 
     
     
       18. The process according to  claim 11 , wherein the enzyme is  Rhizomucor Miehei  Lipase. 
     
     
       19. The process according to  claim 11 , further comprising:
 a) replacing the functional group at position C4 of the compound of formula III with B to produce a compound of formula VIII: 
 
       
         
           
           
               
               
           
         
       
       wherein B is purine or pyrimidine base;
 b) removing group R 12  of said compound of formula VIII; 
 c) recovering a compound of formula IX: 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       20. The process according to  claim 19 , wherein B is 
       
         
           
           
               
               
           
         
       
       R 3  is H, C 1-6  alkyl, C 1-6  acyl and CO—R 9 ; 
       R 9  is H or C 1-6  alkyl; 
       R 4  and R 5  are each independently H, C 1-6  alkyl, bromide, chloride, fluoride, iodide or CF 3 ; and
 R 6 , R 7  and R 8  are each independently H, bromide, chloride, fluoride, iodide, amino, hydroxyl or C 3-6 cycloalkylamino. 
 
     
     
       21. A process according to  claim 11 , wherein R 11  is C 1-12  alkyl and R 12  is CO—C 6-12  aryl. 
     
     
       22. A process according to  claim 11 , wherein R 11  is methyl and R 12  is benzoyl. 
     
     
       23. A process according to  claim 1 , wherein said process is carried out at a pH of 6 to 8, at a temperature in the range of 5 to 50° C., and the concentration of enzyme with respect to the solvent is 1 mg/ml to 100 mg/ml. 
     
     
       24. A process according to  claim 11 , wherein said process is carried out at a pH of 6 to 8, at a temperature in the range of 5 to 50° C., and the concentration of enzyme with respect to the solvent is 1 mg/ml to 100 mg/ml. 
     
     
       25. A process according to  claim 1 , wherein the weight ratio of the amount of enzyme to the amount of the compound of formula II is 1% to 25%. 
     
     
       26. A process according to  claim 1 , wherein the weight ratio of the amount of enzyme to the amount of the compound of formula II is 5% to 10%. 
     
     
       27. A process according to  claim 11 , wherein the weight ratio of the amount of enzyme to the amount of the compound of formula IV is 1% to 25%. 
     
     
       28. A process according to  claim 11 , wherein the weight ratio of the amount of enzyme to the amount of the compound of formula IV is 5% to 10%.